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Vol. 58, Issue 5, 946-953, November 2000
q-Coupled Receptor-Induced
Interleukin-6 mRNA in Vascular Smooth Muscle Cells Involves the Nuclear
Factor of Activated T Cells
Department of Pharmacology and Graduate Program in Molecular and
Systems Pharmacology, Emory University School of Medicine,
Atlanta, Georgia
The immunosuppressant cyclosporin A inhibits transcription mediated by
the nuclear factor of activated T-cells (NFAT), a key regulator
of cytokine gene expression in lymphocytes that integrates phospholipase C signaling. NFAT is also expressed in vascular smooth
muscle cells, but the genes it regulates there are unknown. Here we
show that G
q-coupled P2Y nucleotide receptor
signaling in rat vascular smooth muscle cells increases NFAT-mediated
luciferase reporter expression. It also induces interleukin (IL)-6 gene
expression but not other cytokine mRNAs including IL-1, IL-2, IL-3,
IL-4, IL-10,
-interferon, tumor necrosis factor-
, or tumor
necrosis factor-
. IL-6 mRNA induction by UTP is more rapid and
transient then that caused by IL-1
stimulation and is partially
blocked by cyclosporin A or by expression of a
trans-dominant NFAT inhibitor. Expression of recombinant
NFATc1 markedly augments IL-6 mRNA induction by these and other
agonists, which is partially attributable to NFAT-regulated paracrine
mediators. However, trans-dominant NF
B inhibitors
strongly interfere with IL-6 mRNA induction both by IL-1
and by UTP,
which synergistically evoke IL-6 mRNA expression. These findings
suggest that NFAT is among the cofactors involved in NF
B-dependent
IL-6 gene induction by Ca2+-mobilizing receptors in
vascular smooth muscle cells.
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